Combination Of Gemcitabine Research Articles

FOXM1, a super enhancer-associated gene, is related to poorer prognosis and gemcitabine resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid tumor; however, the barrier of chemoresistance has yet to be overcome for longer survival. Aberrant gene expression due to epigenetic modification plays an important role in tumorigenesis and treatment. Super enhancers are epigenetic elements that promote targeted gene transcription and ultimately lead to chemoresistance. This study found that the expression of FOXM1 was higher in PDAC tissues and negatively correlated with prognosis. Through RNA sequencing and chromatin immunoprecipitation-sequencing analyses, FOXM1 was found to be regulated by a BRD4-associated super enhancer, which finally promoted gemcitabine resistance via TGFβ/Smad signaling pathway activation. Both TGFβ/Smad-specific inhibitor LY364947 and the BRD4 inhibitor JQ1 decreased the IC50 value of gemcitabine in vitro. Furthermore, combined gemcitabine and JQ1 therapy could not only enhance the therapeutic effect of gemcitabine but also reverse drug resistance in vivo. In conclusion, the super enhancer-associated gene FOMX1 contributes to gemcitabine resistance and is a promising target in PDAC treatment.

Immunotherapy engagement in pancreatic adenocarcinoma: Provisional results of iLSTA study— Durvalumab, LSTA1 (certepetide), gemcitabine, and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma.

746 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dense, extracellular matrix-rich stroma, which creates a physical barrier against drug penetration. Evidence suggests that the iRGD peptide, LSTA-1, can increase the penetration of anti-cancer drugs to tumours through selective targeting of tumour endothelial cell receptors. Additionally, LSTA-1 administration promotes CD8+ immune cell tumour infiltration, potentially enabling immunotherapy as a treatment modality. iLSTA examined safety, tolerability and effect of the combination. Methods: Participants diagnosed with locally advanced PDAC were divided into 3 cohorts in a 1:1:4 ratio. Cohort 1 (n=5) received gemcitabine (1000mg/m 2 ), nab-paclitaxel (125mg/m 2 ), placebo LSTA-1 (3.2mg/kg) and placebo durvalumab (750mg). Cohort 2 (n=5) received gemcitabine, nab-paclitaxel, active and placebo LSTA-1, and placebo durvalumab. Cohort 3 (n=20) received gemcitabine, nab-paclitaxel, LSTA-1 and durvalumab. Tissue biopsies via endoscopic ultrasound were obtained pre-treatment and between weeks 12 and 16 for analysis of tumour infiltrating lymphocytes (TILs). Patient tumour sizes were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Results: 6/17 patients showed significant RECIST partial response after 2 cycles of treatment (5 patients in cohort 3), with the remaining 11 patients exhibiting stable disease. After 4 cycles of treatment, 10/17 patients demonstrated partial response (9 patients in cohort 3). Of the remaining 7 patients, 6 demonstrated stable disease, and 1 patient (cohort 2) exhibited a RECIST complete response. 13/17 patients who completed 4 treatment cycles showed a decrease in CA19-9 levels. 6 patients demonstrated >90% reduction in CA19-9 (5 in cohort 3), with the remaining 7 patients showing a >50% reduction in CA19-9 levels (5 in cohort 3). 12 patients underwent repeat biopsies 12-16 weeks post-treatment to assess TILs. 10 patients showed immune cell infiltration (5% to 50% stroma infiltration), 2 had no tumour found (Cohort 3). The combination was safe with no unexpected toxicities. Conclusions: The preliminary results of this study suggest that the combination of gemcitabine and nab-paclitaxel with LSTA-1 and durvalumab is safe and potentially induces tumour infiltrating lymphocytes and RECIST response in locally advanced pancreatic adenocarcinomas. Clinical trial information: ACTRN12623000223639 .

A phase 2 study of amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) in metastatic pancreatic cancer.

TPS790 Background: Patients with advanced pancreatic adenocarcinoma (PDC) that progresses after first-line therapy face limited treatment options. Despite advances in systemic therapy, the prognosis for PDC is dismal, with a five-year overall survival (OS) of about 5% . Due to the high morbidity of this disease, there is a critical need for innovative treatments to improve patient outcomes. TheraBionic P1, a hand-held device, delivers tumor specific radio frequencies via a spoon-shaped antenna placed on the patient's tongue. The FDA and EMA have confirmed the safety of the device for amplitude-modulated electromagnetic field (AM-EMF) therapy. Improved efficacy outcomes were reported with AM RF EMF in other solid organ tumors including pancreatic cancer in preliminary studies. Preclinical and clinical evidence suggests that AM-EMF can inhibit tumor growth and was recently approved for use in hepatocellular cancer. The safety and clinical activity observed with AM RF EMF, paired with the unmet medical need for additional effective therapies in pancreatic cancer, provided a strong rationale for further clinical investigation. This protocol evaluates the efficacy and tolerability of AM RF EMF in combination with standard of care frontline therapy, gemcitabine and nab-paclitaxel for metastatic PDC. Methods: This is an ongoing, single-center, Phase II, non-randomized study using a Simon two-stage minimax design to assess the efficacy of AM-EMF in combination with gemcitabine/nab-paclitaxel as a first-line treatment in metastatic pancreatic cancer. Gemcitabine and nab-paclitaxel are administered per standard care. AM RF EMF are delivered to patients with a spoon-shaped applicator placed on the tongue three daily 60-minute treatments. Patients will be assessed for response every 8 weeks. Treatment is continued until progression or toxicity. The primary objective of this study is to evaluate the efficacy of the combination of nab-paclitaxel, gemcitabine, and AM RF EMF in improving 6-month overall survival rates in patients with metastatic PDC. Secondary objectives evaluate the safety, tolerability, profession free survival, objective response rate and disease control rate. Exploratory objectives evaluate change in CA19-9 and quality of life using FACT-General (FACT-G) and determine any possible correlation with clinical outcomes. Key eligibility includes treatment-naïve, histologically confirmed metastatic PC, age eighteen years old or greater, ECOG 0-1, and optimal organ function. Clinical trial information: NCT05776524 .

A phase II study of peri-operative NovoTTF-200T(P) in combination with gemcitabine and nab-paclitaxel for resectable pancreatic adenocarcinoma: Big Ten Cancer Research Consortium (BTCRC-GI21-500).

TPS795 Background: The recurrence rates and outcomes in resectable pancreatic ductal adenocarcinoma (R-PDA) is concerningly high. The benefit of neoadjuvant chemotherapy over traditional upfront surgery followed by adjuvant therapy is not clear. Electromagnetic fields generate bi-directional forces on highly polar intracellular components, causing abnormal microtubule polymerization during spindle formation and irregular cleavage furrow formation. We will leverage these anti-proliferative effects in managing R-PDA by tumor treating fields (TTF) with chemotherapy backed by strong in vitro and in vivo evidence. The PANOVA phase II trial (n=40) gave us safety and efficacy data of this combination in advanced PDA. No systemic effects were associated with TTF. The only notable safety issue was a small incidence of grade 3 device-related dermatitis. Methods: Our phase II single arm study will investigate perioperative use of TTF with gemcitabine and nab-paclitaxel (G-NP) combination. Eligible patients R-PDA (visible pancreatic mass, measurable disease, absence of arterial interface, venous interface ≤ 180°, patent portal splenic confluence, and no metastatic disease, including lymphadenopathy outside the surgical area) will wear TTF and receive three cycles of G-NP before restaging. Patients are expected to wear TTF for > 80% of the time during this period. If they proceed with resection, additional 3 cycles of Gem-NP with TTF will be given to the patient. This study employs a Bayesian Optimal Phase 2 (BOP2) design with primary endpoints of overall survival (OS) at 2 years and resection rate. The null hypothesis posits a 40% OS rate compared to a target of 60%, and a resection rate null hypothesis of 60% versus a target of 75%. The trial aims to enroll 30 patients, with an interim futility analysis planned after 15 participants. Enrollment will be terminated early if 8 or fewer patients undergo resection in the initial stage, providing 83% power and a type I error rate of 10%. Secondary endpoints include adverse events, overall response rate, TTFields compliance rate, relative dose intensity, and overall survival. The trial started actively recruiting patients in April 2024. The accrual goal is 38 patients. At the time of submission, one patient was enrolled. Clinical trial information: NCT05624918 .

Ossifying fibromyxoid tumours: A case series.

Ossifying fibromyxoid tumour is a rare mesenchymal soft tissue sarcoma with uncertain differentiation and variable metastatic potential. This study offers a retrospective analysis of 23 patients diagnosed with OFMT between 1993 and 2024. The tumours most commonly arose in the extremities and trunk, with all patients undergoing surgical resection of the primary tumour. Immunohistochemical analysis frequently revealed the expression of S100 protein and desmin, while next-generation sequencing identified PHF1 rearrangements in 83 % of patients with available NGS, notably PHF1::EP400 and PHF1::TFE3 fusions. Five patients experienced local recurrence, and four developed metastatic disease. There is no prospective data to guide decision making with regards to systemic therapy, and doxorubicin-based regimens demonstrate limited efficacy. However, the potential role of epigenetic dysregulation in OFMT tumorigenesis opens exciting avenues for treatment. In this cohort, one patient exhibited a remarkably durable response to a combination of gemcitabine, which inhibits DNA methylation, and dacarbazine, following rapid tumour progression on doxorubicin. Given the limited clinical experience with OFMT, multidisciplinary tumour boards are crucial for tailoring individualized treatment strategies. This study contributes to the growing body of literature on OFMT, providing a foundation for future research.

Potential effect of the gut microbiome on tumour response to anti-cancer treatment in patients diagnosed with pancreatic ductal adenocarcinoma.

757 Background: Chemotherapy is the standard of care for pancreatic ductal adenocarcinoma (PDAC), however, recent research has identified bacteria in the human gut microbiome that may influence patient response to chemotherapy. These bacteria are also present in faeces, and are thought to be representative of the bacteria in the pancreatic ductal system. Preliminary studies have suggested that patients with more advanced PDAC demonstrate lower levels of Firmicutes, and higher levels of Proteobacteria. Additionally, research has shown bacteria in the Firmicutes phylum possess several anti-cancer properties, which may improve patient treatment response, meanwhile, Gammaproteobacteria (Proteobacteria phylum), have been shown to attenuate gemcitabine efficacy and worsen treatment response. Methods: This prospective study involved 14 participants with locally advanced PDAC. Participants received combinations of Gemcitabine, Nab-Paclitaxel, and durvalumab (immunotherapy). Participant tumours were assessed every 8 weeks using radiological imaging according to RECIST v1.1, and serum CA19-9 levels were analysed monthly. Gut microbial profiling was completed on stool samples taken pre-treatment using PacBio HiFi full-length 16S rRNA sequencing. Results: 16S rRNA sequencing identified that of the 4 patients that died due to disease progression, 3 patients had a low Firmicutes abundance, and a high Proteobacteria abundance. The rother patient demonstrated low levels of Actinobacteriota and Bacteroidota, and a low bacterial diversity. One participant showed a significant increase in CA19-9 (1066.7%), and exhibited a low abundance of Actinobacteriota and Bacteroidota, a high abundance of Proteobacteria, and a low diversity. 5 participants demonstrated a significant treatment response (according to CA19-9 and RECIST analysis), with 4 patients showing a high Firmicutes abundance, high levels of Actinobacteriota or Bacteroidota, and low levels of Proteobacteria. The remaining patient demonstrated a low abundance of Firmicutes and Proteobacteria, yet, displayed the highest abundance of Actinobacteriota and Bacteroidota. Conclusions: This exploratory study suggests an association between microbial composition and treatment response, with Firmicutes potentially being associated with an improved treatment response, and Proteobacteria with a worsened response. We believe this study to be one of the first to explore correlation of microbiome with clinical treatment response in PDAC.

Case report: PD-L1-targeted high-affinity natural killer cells and IL-15 superagonist N-803-based therapy extend overall survival of advanced metastatic pancreatic cancer patients

BackgroundMetastatic pancreatic cancer (mPC) is an aggressive form of cancer with a poor prognosis and few therapeutic options after failure of the second-line treatment. Induction of immunogenic cell death (ICD) by use of relatively low-dose chemo- or radiation therapy, enhancement of immune responses by the IL-15 superagonist N-803 (Anktiva®), and targeting of programmed death receptor ligand 1 (PD-L1)-expressing cells may offer a therapeutic approach to refractory mPC with the potential to increase overall survival (OS).MethodsFrom late 2019 to 2021, single-patient Investigational New Drug (spIND) protocols for five mPC patients were designed and approved that generally comprised combined Abraxane (nab-paclitaxel) and gemcitabine therapy with experimental therapeutics N-803, PD-L1-targeted high-affinity natural killer (PD-L1 t-haNK) cells, and aldoxorubicin, a serum albumin-binding doxorubicin prodrug. Some patients also received stereotactic body radiation therapy (SBRT), cyclophosphamide, pembrolizumab, nivolumab, and/or experimental ETBX-051 (brachyury) and/or ETBX-061 (MUC1) vaccines. Duration of spIND treatment and responses, for some patients including imaging and carbohydrate antigen 19-9 (CA19-9) levels, and OS from initial diagnosis and the start of spIND therapy were assessed.FindingsThe line/duration of spIND therapy was, for patients 1 through 5, respectively, second line/6.4 months, sixth line/3.5 months, third line/25.4 months, third line/7.4 months, and fourth line/23.2 months. OS from the commencement of spIND therapy was 13, 4.8, 26.9, 9, and 23.2 months, and OS from diagnosis was 22, 21, 42, 13, and 33 months for patients 1 through 5, respectively.ConclusionsThe OS from the initiation of spIND for all patients exceeded the reported OS for the greater-than-second-line mPC patients and, for four of five patients, second-line therapy. The OS of 13, 26.9, and 23.2 months for three patients is particularly notable. The findings here support the ongoing clinical investigations of N-803 and PD-L1 t-haNK cells in combination therapy.

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.

The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

The role of mitochondrial dysfunction in the cytotoxic synergistic effect of gemcitabine and arsenic on breast cancer.

Breast cancer is the most common type of cancer in women worldwide. A common approach to cancer treatment in clinical practice is to use a combination of drugs to enhance the anticancer activity of drugs while reducing their side effects. In this regard, we evaluated the effectiveness of combined treatment with gemcitabine (GCB) and arsenic (ATO) and how they affect the cell death pathway in cancer cells. Cytotoxic activity of drugs individually or combined against MDA-MB-231 and MCF-7 was performed by MTT method and isobolographic analysis was used to determine the interaction between these factors. The combination of ATO and GCB showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines. The combination of ATO and GCB induced sub-G1 phase arrest, apoptosis and death rates in MCF-7 and MDA-MB-231 cells. The apoptotic response induced by the combination of GCB and ATO was dependent on caspase 3/7. Combined treatment with mitochondrial membrane potential (MMP) reduction and increased reactive oxygen species (ROS) production caused mitochondrial dysfunction. Co-treatment significantly reduced catalase (CAT) activity in both cancer cells compared to the control group and cells treated with each monotherapy. A significant decrease in cellular GSH was observed in cancer cells treated with ATO and GCB. In addition, migration and invasion were significantly reduced in breast cancer cells treated with the combination of ATO and GCB compared to cells treated with ATO and GCB. In conclusion, the combined treatment of ATO and GCB synergistically increased the anti-cancer activity, and these findings provide an effective approach for the treatment of breast cancer. To the best of our knowledge, this is the first study showing promising results for combination therapy with ATO and GCB in breast cancer.

Niraparib perturbs autophagosome-lysosome fusion in pancreatic ductal adenocarcinoma and exhibits anticancer potential against gemcitabine-resistant PDAC

While poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have achieved specific clinical benefits in a subset of pancreatic ductal adenocarcinoma (PDAC) patients, the potential role of the PARPi niraparib in PDAC necessitates further exploration. In this study, we demonstrated that Niraparib exhibited a pronounced inhibitory effect on autophagy in PDAC both in vitro and in vivo. Mechanistically, this inhibition was primarily attributed to niraparib's ability to disrupt the fusion process between autophagosomes and lysosomes, while potentially exerting a relatively minor impact on the initial stage of autophagy. The blockade effect observed may be mediated via modulation of the ERK signaling pathway, and this effect can be mitigated by the application of an ERK inhibitor (FR180204). Notably, the combined treatment regimen of niraparib and gemcitabine failed to elicit the anticipated synergistic effects in wild-type PANC-1 cells, instead exhibiting pronounced antagonistic interactions. However, in gemcitabine-resistant PANC-1 cells, the combination of niraparib and gemcitabine exhibited modest additive effects. Furthermore, niraparib demonstrated a heightened cytotoxic potency against gemcitabine-resistant PANC-1 cells compared to wild-type PANC-1 cells, both in vitro and in vivo. Our research established that niraparib inhibits late-stage autophagy in PDAC, potentially representing a valuable salvage therapy for gemcitabine-resistant PDAC. Further clinical studies are justified.

Systemic Therapy in Metastatic Pancreatic Cancer: A Review

The prognosis for pancreatic cancer is still poor, because it is typically identified at an advanced, frequently metastatic stage. Recently, a sequential treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC) has been developed. When the performance status is good, combination chemotherapy regimens such FOLFIRINOX and gemcitabine plus nab-paclitaxel are options for first-line treatment. Gemcitabine monotherapy is a viable choice for patients with lower performance status. Recently, olaparib, a PARP inhibitor, was showed to enhance the amount of time patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a BRCA1/-2 germ line mutation can live without their disease worsening. If the initial treatment is unsuccessful, patients should be provided with an alternative treatment option if their ECOG score allows for continued treatment. The combination of 5-FU/FA with nanoliposomal irinotecan has demonstrated better overall survival compared to 5-FU/FA alone. Immune checkpoint drugs like PD1/PD-L1 mAbs are particularly efficacious in malignancies with high microsatellite instability (MSI-h). Limited data in mPDACs suggests that only a part of the already tiny subgroup of MSI-H mPDACs (frequency approximately 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of other subgroups, may further increase therapeutic efficacy.

The combination of gemcitabine and albumin-bound paclitaxel effectively inhibits de novo lipogenesis in pancreatic cancer cells by targeting the AMPK/SREBP1 pathway.

Abnormal lipid de novo lipogenesis and reprogramming of lipid metabolism have been associated with the development and progression of various cancers, including pancreatic cancer. Gemcitabine (GEM) combined with albumin-bound paclitaxel (nab-PTX) is the first-line chemotherapeutic agent for pancreatic cancer. There have been many studies on the molecular mechanisms of gemcitabine and paclitaxel in cancer treatment. Still, the effects of the combination on lipid metabolism and the specific mechanisms have not been explored. This study found that GEM combined with nab-PTX inhibited pancreatic cancer cell proliferation and de novo lipogenesis. The exact mechanism is that GEM combined with nab-PTX induces adenosine triphosphate (ATP) depletion and activates AMP-activated protein kinase (AMPK) in pancreatic cancer cells, which in turn inhibits sterol regulatory element-binding protein 1 (SREBP1) expression and nuclear translocation, and ultimately inhibits de novo lipogenesis in pancreatic cancer cells. In addition, we found that the novel lipid-lowering drug ETC-1002 significantly enhanced the inhibitory effect of GEM combined with nab-PTX on de novo lipogenesis in pancreatic cancer cells. These findings establish a link between GEM combined with nab-PTX and lipid metabolism, and the discovery of the novel lipid-lowering drug ETC-1002 provides a potential therapeutic strategy for pancreatic cancer.

Pembrolizumab (MK-3475) plus platinum and gemcitabine as first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (PIPER): a phase 2, multicentre, single-arm protocol study in Malaysia

IntroductionTreatment combination of pembrolizumab plus platinum and 5-fluorouracil (PF) has increased the survival of recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The combination of platinum and...

3D bioprinting of multicellular tumor spheroids in photocrosslinkable hyaluronan-gelatin for engineering pancreatic cancer microenvironment

3D bioprinting can be utilized to fabricate cancer-like tissue that models complex interactions within the cancer microenvironment. In human pancreatic ductal adenocarcinoma (PDAC), these interactions involve the extracellular matrix (ECM), cancer cells, and pancreatic stellate cells. Hyaluronan (HA) is a major component of ECM supporting tumor progression and chemoresistance in PDAC. In the current study, an in vitro PDAC-like tissue platform was developed by embedding multicellular pancreatic tumor-like spheroids within a novel 3D bioprinting HA-gelatin photocrosslinked hydrogel (GHP). This optimized GHP bioink (7 wt% gelatin and 0.2 wt% phenolic HA) achieved a modulus (∼5.46 kPa) closely resembling that of clinical PDAC tissue, with a dense and uniform structure superior to gelatin-only hydrogel (GN). The bioprinted 3D tumor-like spheroids within GHP exhibited distinct invasive and metastatic behavior, along with up-regulated expression of epithelial-mesenchymal transition (EMT) markers. Furthermore, gene expression analysis also revealed a ∼290-fold increase in CD44 gene and a 7.3-fold rise in S100A9 (a novel pancreatic cancer biomarker for early diagnosis). These tumor-like spheroids within 3D-bioprinted GHP constructs further demonstrated substantial chemoresistance, maintaining remarkable 98.5% viability after 48 h of exposure to a Gemcitabine and Abraxane combination, in contrast to significantly lower resistance observed in spheroids alone or co-cultured monolayers. An in-depth investigation of HA distribution within the 3D-bioprinted PDAC-like construct revealed a pattern consistent with clinical PDAC, indicating enhanced malignancy and potential tumor reprogramming. This 3D-bioprinted PDAC model holds significant potential for advancing pancreatic cancer research and preclinical drug testing.

Camrelizumab combined with gemcitabine and apatinib in treating advanced PD-L1-positive biliary tract cancers.

The efficacy of combined chemotherapy and immunotherapy has previously been demonstrated in patients with biliary tract cancer. The aim of this study was to assess the efficacy and safety of camrelizumab in combination with gemcitabine and apatinib as a first- or second-line treatment for advanced programmed death-ligand 1 (PD-L1)-positive biliary tract cancer. This prospective, single-arm, and exploratory clinical trial aimed at recruiting 20 PD-L1-positive patients (tumor proportion score ≥1% or combined positive score ≥1) who met the inclusion criteria. Camrelizumab (200 mg) was administered in combination with gemcitabine (800 mg/m2) and apatinib (250 mg). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Fourteen patients were enrolled between September 2, 2020, and December 15, 2022. At the data cutoff on August 16, 2023, the median follow-up time was 11.4 months (interquartile range, 4.5-15.4), with one patient still undergoing treatment. Among the enrolled patients, six achieved a partial response, and four had stable disease. The ORR was 42.9% (95% confidence interval [CI], 17.7-71.1), and the DCR was 71.4% (95% CI, 41.9-91.6). The median PFS was 5.4 months (95% CI, 2.8-not reached), and the median OS was 13.5 months (95% CI, 5.7-not reached). The most frequent grade 3 or 4 treatment-related adverse event was neutropenia (n = 4, 29%). The combination of camrelizumab, gemcitabine, and apatinib showed promising efficacy and acceptable safety in patients with advanced PD-L1-positive biliary tract cancer.

Multiple Sclerosis and Subcutaneous Panniculitis-like T Cell Lymphoma with Hemophagocytic Syndrome: The Role of Treatment Sequencing in the Pathogenetic Mechanism

Introduction: Although panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) have been described as complications following immunosuppressive treatments, there are no reported cases of concomitant SPTCL/HSP and multiple sclerosis (MS). Materials and Methods: We describe the case of a patient affected by an aggressive phenotype of relapsing remitting MS, characterized by consecutive severe relapses with no complete remission. He developed panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) after receiving multiple immunosuppressive treatments in sequence. Despite the aggressive nature of these complications, the patient responded well to a combination of Gemcitabine and Cisplatin. Discussion and Conclusions: With this case, we suggest that physicians always consider blood diseases as possible MS therapy complications, especially in the sequencing setting, and also consider uncommon treatments in those with autoimmune predispositions.

Phase 2 trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (EAGLES, Korean Cancer Study Group UN18-09).

In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy. Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR). In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n=3; hepatitis, n=2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p=.104), progression-free survival (median, 7.3 vs. 3.3 months; p=.024), and overall survival (median, not reached vs. 21.5 months; p=.027). The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy.

Phase II Trial of Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.

The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease. A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression. Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.

A meta-analysis and systematic review of randomized controlled trials in combination gemcitabine with erlotinib in the pancreatic cancer.

Previous studies have demonstrated the efficacy and safety of combining gemcitabine and erlotinib (Gem-Erlo) for the treatment of pancreatic cancer (PaC). However, there is a limited number of clinical studies and multiple prospective randomized controlled trials (RCTs) have yielded inconsistent conclusions. The question of whether Gem-Erlo has significant advantages over conventional chemotherapy in the treatment of PaC has been controversial. In order to provide valuable insights for PaC treatment, this study conducted a meta-analysis based on the current evidence from RCTs. We searched several databases including PubMed/Medline, Web of Science, Cochrane Library, and Embase, as well as relevant conference abstracts from the beginning of their inception to July 2023. We used the patient/population, intervention, comparison, outcomes and study design (PICOS) principle to screen the literature. After title, abstract and full text filtering, we extract the data from each study to assess the risk of bias by examining the quality of the literature. We used a meta-analysis with random effects model to synthesize and summarize the results regarding objective response rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS) and 1-year survival rate. Seven RCTs were included, involving 2,152 PaC patients treated with either Gem-Erlo or gemcitabine alone. The results showed that Gem-Erlo significantly improved DCR [odds ratio (OR) =1.74; 95% confidence interval (CI): 1.03 to 2.92; P=0.04]; but did not significantly improve median OS [standardized mean difference (SMD) =-0.20; 95% CI: -1.46 to 1.06; P=0.75], median PFS (SMD =-0.97; 95% CI: -4.01 to 2.07; P=0.53), ORR (OR =1.29; 95% CI: 0.84 to 1.97), or 1-year survival rate (OR =1.18; 95% CI: 0.88 to 1.57). In addition, sensitivity analysis of the median OS showed the Gem-Erlo group significantly prolonged the median OS compared to the gemcitabine alone group [weighted mean difference (WMD) =-1.74; 95% CI: -1.87 to -1.62; P<0.001]. The most common adverse events (AEs) were rash, diarrhea, fatigue, neutropenia and thrombocytopenia in both groups, but the Gem-Erlo group is more often than the gemcitabine alone (OR =1.40, 95% CI: 1.19 to 1.65; P<0.001), and all AEs were within the acceptable range for patients. Gem-Erlo can improve DCR when compared to gemcitabine. There was no statistically significant improvement in median PFS, median OS, ORR and 1-year survival rate. However, sensitivity analysis showed a statistical difference in the median OS. Our study indicated that Gem-Erlo had better efficacy than gemcitabine alone in PaC therapy. The occurrence of AEs is under the acceptable range for patients.

Initial adjustments in the dosage and rest period of gemcitabine plus cisplatin therapy for patients with incurable biliary tract cancer based on baseline estimated glomerular filtration rate (eGFR) values may be crucial for treatment outcomes and the preservation of renal function.

Gemcitabine (GEM) and cisplatin (CDDP) combination therapy (GC therapy) is the standard 1st-line regimen for incurable biliary tract cancers (BTCs). However, the correlation between dynamic changes in renal function and the outcomes of GC therapy remains unclear. This study aimed to clarify the association between renal function alterations and treatment outcomes after GC therapy. We retrospectively examined 44 patients with incurable BTC who underwent GC therapy (January 2015 to December 2022). The patients were stratified according to their baseline estimated glomerular filtration rate (eGFR). Changes in eGFR, overall survival (OS), and progression-free survival (PFS). The median baseline eGFRs were 65.0 mL/min/1.73 m2 (low group, n=22) and 90.7 mL/min/1.73 m2 (high group, n=22). No significant background differences were observed between the groups. During the 1st course, 86.4% and 54.5% of patients in the low and high groups underwent dose adjustments and/or administration postponement, which was found to be significantly greater in the low group. In the high group, eGFR decreased with an increase in the CDDP dose (100 mg =-12.0, 200 mg =-12.7, 300 mg =-25.9, and 400 mg =-25.7 mL/min/1.73 m2). In the low group, eGFR remained stable (100 mg =0.8, 200 mg =7.5, 300 mg =4.5, and 400 mg =-0.3 mL/min/1.73 m2). The decrease in the eGFR in the high group was significantly greater at each CDDP dose. However, the median OS and PFS were longer in the low group (OS: 16.3 vs. 9.2 months, P=0.02; PFS: 5.4 vs. 3.6 months, P=0.02). No significant differences in adverse events were observed between the groups. Adjusting GC therapy based on baseline estimated glomerular eGFR may be pivotal for therapeutic benefits and renal function protection in patients with incurable BTC.